The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide, infecting an estimated 170 million persons. Antiviral research directed toward the development of improved treatment methods for chronic HCV infections has focused mainly on inhibitors of the NS5B polymerase. See e.g., Brown, N. A., 2009, Expert Opin. Investig. Drugs 18:709-725. Indeed, treatment of hepatitis C virus (HCV) infection remains an important unmet medical need due to the inadequacies of current interferon-based therapy. See e.g., Falck-Ytter, Y., et al., 2003, Ann. Intern. Med., 136:288-292. In the United States there are 3 to 4 million persons with chronic HCV infection. See e.g., Armstrong, G. L., et al., 2006, Ann. Intern. Med., 144:705-714. A number of agents are currently in clinical development for HCV including NS3 protease inhibitors and NS5B antiviral nucleosides and non-nucleoside polymerase inhibitors. See e.g., Sarrazin, C. & Zeuzem, S., 2010, Gastroenterology, 138:447-462. Clinical and in vitro data indicate that resistance develops readily with protease and non-nucleoside polymerase inhibitors. See e.g., Sarrazin, C, et al., 2007, Gastroenterology, 132:1767-1777; McCown, M. F., et al., 2009, Antimicrob. Agents Chemother., 53:2129-2132; Howe, A. Y. M, et al., 2008, Antimicrob. Agents Chemother., 52:3327-3338. Nucleoside inhibitors which target the catalytic site of the NS5B RNA dependent RNA polymerase have been shown to be active across different HCV genotypes. See e.g., McCown M. F., et al., 2008, Antimicrob. Agents Chemother., 52:1604-1612.
A current therapy for chronic hepatitis C includes combination treatment with weekly injections of pegylated alpha-IFN (pegIFN) and daily oral ribavirin (RBV) administration. PegIFN/RBV treatment is effective in >75% of patients infected with HCV genotype-2 (HCV-2) and genotype-3 (HCV-3), but most patients in North America, Europe and Japan are infected with HCV genotype-1 (HCV-1) and only about 40-50% of HCV-1 patients respond to therapy with pegIFN/RBV.
There are currently only a few anti-HCV nucleosides in clinical studies. See Table A.
TABLE ASelected HCV polymerase and protease inhibitors indevelopment taken from (Brown, N. A., Expert Opin.Investig. Drugs 18: 709-725 (2009)).CompoundNucleosideHCV NS5BPolymeraseDevelopmentInhibitors (NIs)SponsorphaseCommentNM283Idenix-NovartisIIbDevelopment(valopicitabine)discontinued 2007R1626RocheIIaProdrug of R1479;developmentdiscontinued 2008R7128Pharmasset-RocheIIaProdrug of PSI-6130IDX184IdenixIbPhase Ia data inhealthy volunteersMK-0608MerckLatepreclinicalPSI-7851PharmassetIaPreclinical data≧3 othersVarious sponsorsPreclinicalNo data available
Some acyclic nucleoside phosphonates (ANPs) are antiviral agents with activity against double stranded DNA (dsDNA) viruses, or viruses which rely on reverse transcription such as HBV and HIV-1. See e.g., Hostetler K. Y., 2009, Antiviral Res., 82:A84-98; Morrey, J. D. 2009, Antimicrob. Agents Chemother., 53:2865-2870; Hostetler, K. Y., et al., 2006, Antimicrob. Agents Chemother., 50:2857-2859. We previously reported that octadecyloxyethyl 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (ODE-(S)-HPMPA, 1) exhibited antiviral activity against genotype 1b and 2a HCV replicons. See e.g., Wyles, D. L., et al., 2009, Antimicrob. Agents Chemother., 53:2660-2662. Some acyclic nucleoside phosphonates of this class (i.e., HPMP series) are broad spectrum anti-DNA virus agents. See e.g., De Clercq, E., 2007, Biochem. Pharmacol. 73:911-922. Some compounds of this class have been reported to be inactive against RNA viruses, including HCV. See e.g., Holý, A., 2006, Antiviral Res. 71:248-253. ODE-(S)-HPMPA has shown cytotoxicity. See e.g., Wyles et al., 2009, Id.; Beadle, J. R., et al., 2006, J. Med. Chem., 49:2010-2015.
Koh et al. prepared 2′-C-methyl phosphonate analogs of adenosine (Koh, Y., et al., 2005, J. Med. Chem. 48:2867). Others have reported phosphonates with weak anti-HCV activity. See e.g., Mackman, “Synthesis and antiviral activity of 4′-modified carbocyclic nucleoside phosphonates (CNPs),” Collection Symposium Series 10:191 (2008); Sheng, X. C. et al., 2009, Bioorg. Med. Chem. Lett. 19:3453-3457.
There is a need for improved anti-HCV therapeutic agents, i.e. drugs having improved antiviral and pharmacokinetic properties with enhanced activity against development of HCV resistance, improved oral bioavailability, greater efficacy and fewer undesirable side effects. The present invention provides solutions for these and other needs in the art. For example, we have found, inter alia, that derivatives of ODE-(S)-HPMPA modified by alkylation of the acyclic side chain hydroxyl are surprisingly potent inhibitors of HCV replication in vitro and importantly are much less toxic than ODE-(S)-HPMPA both in vitro and in vivo in mice.